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Disruption of Fusion Results in Mitochondrial Heterogeneity and Dysfunction
Open accessAbstract
Mitochondria undergo continual cycles of fusion and fission, and the balance of these opposing processes regulates mitochondrial morphology. Paradoxically, cells invest many resources to maintain tubular mitochondrial morphology, when reducing both fusion and fission simultaneously achieves the same end. This observation suggests a requirement for mitochondrial fusion, beyond maintenance of organelle morphology. Here, we show that cells with targeted null mutations in Mfn1 or Mfn2 retained low levels of mitochondrial fusion and escaped major cellular dysfunction. Analysis of these mutant cells showed that both homotypic and heterotypic interactions of Mfns are capable of fusion. In contrast, cells lacking both Mfn1 and Mfn2 completely lacked mitochondrial fusion and showed severe cellular defects, including poor cell growth, widespread heterogeneity of mitochondrial membrane potential, and decreased cellular respiration. Disruption of OPA1 by RNAi also blocked all mitochondrial fusion and resulted in similar cellular defects. These defects in Mfn-null or OPA1-RNAi mammalian cells were corrected upon restoration of mitochondrial fusion, unlike the irreversible defects found in fzodelta yeast. In contrast, fragmentation of mitochondria, without severe loss of fusion, did not result in such cellular defects. Our results showed that key cellular functions decline as mitochondrial fusion is progressively abrogated.
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“fibroblasts lacking Mfn1 and Mfn2 completely lack mitochondrial fusion and show severe cellular defects, including poor growth, heterogeneity of mitochondrial membrane potential, and decreased respiration (11).”
From Mitochondrial Fission Contributes to Mitochondrial Dysfunction and Insulin Resistance in Skeletal Muscle (2012) · cites this paper as [11]
In the citing paper
“This is of particular importance since it is now established that mitochondrial morphology and function are interrelated, with changes in mitochondrial morphology affecting mitochondrial function (Chen et al., 2005; Jahani-Asl et al., 2007; Yu et al., 2008; Ong et al., 2010; Gomes et al., 2011) and vice versa (Benard et al., 2007).”
From Effects of Aging and Caloric Restriction on Fiber Type Composition, Mitochondrial Morphology and Dynamics in Rat Oxidative and Glycolytic Muscles (2019) · cites this paper as Chen et al., 2005
In the citing paper
“Repression of Mfn2 in cells decreases oxygen consumption, glucose oxidation, mitochondrial membrane potential and the expression of oxidative phosphorylation proteins (Bach et al., 2003; Chen et al., 2005; Pich et al., 2005).”
From New insights into the role of mitochondria in aging: mitochondrial dynamics and more (2010) · cites this paper as Chen et al., 2005
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Role of Mitofusin 2 in the Renal Stress Response
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“Moreover, a very recent report from David Chan’s group [5] demonstrates that the mitochondrial fusion defects in Mfn-deficient cells may be accompanied by severe perturbations of cellular growth, respiration, and mitochondrial membrane potential.”
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“For matrix and outer membrane proteins fast and thorough mixing after mitochondrial fusion has been reported (Ishihara et al. 2003, Chen et al. 2005).”
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Sarnataro, R., Velasco, C. D., Monaco, N., Kempf, A., & Miesenböck, G. (2025) · Nature · doi:10.1038/s41586-025-09261-y · Cited by 62
“…the balance between mitochondrial fission and fusion are part of a feedback mechanism that corrects mismatches between NADH supply and ATP demand 36,44,45 that cause sleep pressure to rise or fall, then the experimental induction of these homeostatic responses in dFBNs should move the set points…”
Intersection of mitochondrial fission and fusion machinery with apoptotic pathways: Role of Mcl‐1
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“As showed by Chen and co-workers, downregulation of both Mfn1 and Mfn2 leads to greatly reduced levels of mitochondrial fusion with a highly fragmented mitochondrial population in mutant cells caused by on-going mitochondrial fission (Chen et al., 2005).”
BackgroundInfluentialNew Mechanisms and Targets of Subarachnoid Hemorrhage: A Focus on Mitochondria
Zhang, Z., Zhang, A., Liu, Y., Hu, X., Fang, Y., Wang, X., Luo, Y., Lenahan, C., & Chen, S. (2021) · Current Neuropharmacology · doi:10.2174/1570159x19666211101103646 · Cited by 62
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“Nonetheless, Opa1 inactivity reduces cell proliferation (Chen et al., 2005; Merkwirth et al., 2008).”
Distribution and Apoptotic Function of Outer Membrane Proteins Depend on Mitochondrial Fusion
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“It has been shown that Mfn1/ 2 / and Opa1 / cells have mitochondria lacking DJm and evince other bioenergetic defects (Chen et al., 2003, 2005) which can reduce or eliminate the organelle’s ability to import various factors, the lack of which factors may cause further degradation of the viability…”
InfluentialAllemailem, K. S., Almatroudi, A., Alsahli, M. A., Aljaghwani, A., El-Kady, A. M., Rahmani, A. H., & Khan, A. A. (2021) · International Journal of Nanomedicine · doi:10.2147/ijn.s303832 · Cited by 61
Orexin system is expressed in avian muscle cells and regulates mitochondrial dynamics
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“Mitochondrial number and morphology are controlled by an equilibrium of mitochondrial fusion and fission (Chan, 2006) that is vital for metabolism, energy production, Ca2+ signaling, ROS production, apoptosis, and senescence (Chen et al., 2005; McBride et al., 2006; Yu et al., 2006).”
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“Fusion and fission are cellular events that participate in the maintenance of mitochondrial morphology and its network dynamics [9].”
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“Both MFNs are involved in mitochondrial fusion process by forming homotypic and heterotypic interactions with the inner mitochondria membrane’s (IMM) OPA1 protein [31,32].”
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“Inhibited fusion or unopposed fission yields another morphology, fragmentation of the mitochondrial network (11).”
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“These results indicate that premature senescencerelated bioenergetic alterations in mitochondrial fusion and fission dynamics play a causative role in mitochondrial dysfunction of auditory cells, supporting the idea that disruption of mitochondrial fusion results in mitochondrial dysfunction.(32,33) Taken together, th…”
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RLR-mediated antiviral innate immunity requires oxidative phosphorylation activity
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Two separate functions of NME3 critical for cell survival underlie a neurodegenerative disorder
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“Mfn1-null MEFs display a pattern of mitochondrial fragmentation distinct from that observed in Mfn2-null MEFs [14,15].”
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“The OPA1 protein plays an important role in regulating mitochondrial inner membrane fusion [13,14,15,16] and blocking the release of cytochrome c to prevent apoptosis [15].”
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“This “content mixing” allows the replacement of damaged material, such as mtDNA that harbors mutations, contributing to the suppression of further damage and mitochondrial homogeneity [8, 9].”
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“During cell division, mitochondrial fission evenly partitions mitochondria into daughter cells, whereas mitochondrial fusion is the joining of mitochondria to create an interconnected network for the distribution of mitochondrial proteins and DNA [138,139].”
BackgroundDaily mitochondrial dynamics in cone photoreceptors
Giarmarco, M. M., Brock, D. C., Robbings, B. M., Cleghorn, W. M., Tsantilas, K. A., Kuch, K. C., Ge, W., Rutter, K. M., Parker, E. D., Hurley, J. B., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2007827117 · Cited by 57
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“This suggests that the Mfn2 could serve as the receptor for Parkin at the outer membrane (Chen and Dorn, 2013).”
BackgroundInfluentialLoss of Yme1L perturbates mitochondrial dynamics
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“Greatly high expression of OPA1 in cells results in mitochondrial fragmentation and increases ‘kiss-and-run’ type of mitochondrial fusion.(6,25,26) To check the role of OPA1 in shYme1L-induced mitochondrial fragmentation, we slightly increased the protein level of OPA1 by expressing OPA1 isoform_1 in MEFs, and the exp…”
BackgroundGet the balance right: Mitofusins roles in health and disease
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“OPA1 has been identified as another critical factor governing mitochondrial fusion [35,46].”
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“Another process required for cytochrome c release is cristae remodeling that is coordinated with the OPA1 processing independently of Bax-mediated outer membrane pore formation (Cipolat et al., 2006).”
Mitochondrial dynamics: biology and therapy in lung cancer
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“Mitofusin-1 (MFN1) Fusion GTPase protein, mediates inner mitochondrial membrane fusion Inner mitochondrial membrane [48,49]”
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Abdelwahid, E., Rolland, S. G. M., Teng, X., Conradt, B., Hardwick, J. M., & White, K. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2010.10.008 · Cited by 57
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“Consequently, defects in mitochondrial fusion lead to mitochondrial fragmentation and loss of mitochondrial DNA [26], reduced growth, decreased mitochondrial membrane potential (ΔΨm), and defective respiration [27].”
BackgroundMitochondrial dynamics changes with age in an APPsw/PS1dE9 mouse model of Alzheimer’s disease
Xu, L., Shen, Y., Wang, X., Wei, L., Wang, P., Yang, H., Wang, C.-F., Xie, Z., & Bi, J. (2017) · Neuroreport · doi:10.1097/wnr.0000000000000739 · Cited by 55
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Paclitaxel inhibits mRNA transport in axons
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“Lack or malfunction of the fusion andfissionmachinery results in alteration ofmitochondrialmorphology and energetic failure (Chen et al., 2005; Reddy et al., 2011; Wang et al., 2012).”
BackgroundDasgupta, A., Wu, D., Tian, L., Xiong, P. Y., Dunham‐Snary, K. J., Chen, K., Alizadeh, E., Motamed, M., Potus, F., Hindmarch, C. C. T., et al. (2020) · Comprehensive physiology · doi:10.1002/cphy.c190027 · Cited by 64
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“Chronic levels of stress however, result in extensive fragmentation of mitochondria, decrease in their copy number and lowered respiratory capacity [25-26].”
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“Disorders of mitochondrial dynamics can 74 lead to reduced mitochondrial respiratory capacity (Bach et al. 2003; Chen et al. 2005; Parone et 75 al.”
BackgroundDiet-dependent gut microbiota impacts on adult neurogenesis through mitochondrial stress modulation
Ribeiro, M. F., Santos, A. A., Afonso, M. B., Rodrigues, P. M., Santos, S. S., Castro, R. E., Rodrigues, C. M. P., & Solá, S. (2020) · Brain Communications · doi:10.1093/braincomms/fcaa165 · Cited by 56
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“Mtfn2 and Optic atrophy protein (Opa) 1, resulting in altered mitochondrial structures and respiration.(78,79) Small, mobile mitochondria are needed for rapid distribution of ATP to subcellular sites with high energy demand,(80,81)”
BackgroundOptimal Dynamics for Quality Control in Spatially Distributed Mitochondrial Networks
Patel, P. K., Shirihai, O. S., & Huang, K. C. (2013) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003108 · Cited by 54
Mitochondrial–nuclear epistasis: Implications for human aging and longevity
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“Mitochondrial fragmentation or elongation has been observed depending on the experimental system (Olichon et al. 2003, 2007; Chen et al. 2005; Piquereau et al. 2012; Agier et al. 2012).”
BackgroundMolecular mechanisms of mitochondrial quality control
Li, W., Gui, Y., Guo, C., Huang, Y.-T., Liu, Y., Yu, X., Zhang, H., Wang, J., Liu, R., Mahaman, Y. A. R., et al. (2025) · Translational Neurodegeneration · doi:10.1186/s40035-025-00505-5 · Cited by 57
“This may result from impaired mtDNA distribution during fusion-fis-sion cycles and compromised oxidative phosphorylation efficiency due to disrupted cristae architecture [30, 34].”
Characterization of the mitofusin 2 R94W mutation in a knock‐in mouse model
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“Mitochondrial fusion has also been shown to be necessary for maintenance of membrane potential and respiration (Chen et al., 2005).”
BackgroundMitochondrial Dynamics: An Emerging Paradigm in Ischemia-Reperfusion Injury
Calo, L., Dong, Y., Kumar, R., Przyklenk, K., & Sanderson, T. H. (2013) · Current Pharmaceutical Design · doi:10.2174/138161281939131127110701 · Cited by 53
Aberrant Drp1-mediated mitochondrial division presents in humans with variable outcomes
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The systems biology of mitochondrial fission and fusion and implications for disease and aging
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“Fission increases variability by dividing mitochondria into uneven sized daughters, and fusion reduces this variability by intermixing the mitochondrial content (Chen et al. 2005; Mazzoni and Falcone 2011) (Fig.”
BackgroundMitochondrial dysfunction in glaucomatous degeneration
Zhang, Z.-Q., Chen, S., & Zhang, X. (2023) · International Journal of Ophthalmology · doi:10.18240/ijo.2023.05.20 · Cited by 56
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Possible Role of Mitochondrial Remodelling on Cellular Triacylglycerol Accumulation
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The emerging role of skeletal muscle mitochondrial dynamics in exercise and ageing
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Mitofusin-2 Regulates Platelet Mitochondria and Function
Jacob, S. P., Kosaka, Y., Bhatlekar, S., Denorme, F., Benzon, H., Moody, A., Moody, V., Tugolukova, E. A., Hull, G., Kishimoto, N. Y., et al. (2023) · Circulation Research · doi:10.1161/circresaha.123.322914 · Cited by 51
“65 In line with this, mitochondrial morphology was visibly tipped toward fission in mouse megakaryocytes with deletion of Mfn2.”
BackgroundAcidosis orchestrates adaptations of energy metabolism in tumors
Groessl, S., Kalis, R., Snaebjornsson, M. T., Wambach, L., Haider, J., Andersch, F., Schulze, A., Palm, W., & Zuber, J. A. (2025) · Science · doi:10.1126/science.adp7603 · Cited by 58
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“As previously reported, our model proposes a strong connection between DYm and nonnetworked states of mitochondrial morphology, fragmentation in particular ([55], Figure 10C).”
BackgroundA metabolic perspective on CSF-mediated neurodegeneration in multiple sclerosis
Wentling, M., Gomez, C. L., Park, H.-J., Amatruda, M., Ntranos, A., Aramini, J. M., Petracca, M., Rusielewicz, T., Chen, E., Tolstikov, V., et al. (2019) · Brain · doi:10.1093/brain/awz201 · Cited by 51
Mitochondrial Membrane Remodeling
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“Hence, defects in mitochondrial fusion caused by loss of Mfn1 or Mfn2 can be rescued by overexpressing Mfn2 or Mfn1, respectively (Chen et al., 2005).”
BackgroundAkita, M., Suzuki‐Karasaki, M., Fujiwara, K., Nakagawa, C., Soma, M., Yoshida, Y., Ochiai, T., Tokuhashi, Y., & Suzuki‐Karasaki, Y. (2014) · International Journal of Oncology · doi:10.3892/ijo.2014.2608 · Cited by 50
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Role of Mitofusins and Mitophagy in Life or Death Decisions
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hNOA1 Interacts with Complex I and DAP3 and Regulates Mitochondrial Respiration and Apoptosis
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“Also, defects in mitochondrial fusion are associated with reduced respiration and loss of mitochondrial membrane potential (MMP/1Ψ ) in human peripheral blood mononuclear cells (PBMC) (Chen et al., 2005).”
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Bcl-2 family proteins and mitochondrial fission/fusion dynamics
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Mitochondrial dynamics in aging and disease
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“In addition, mitochondrial fusion presumably regulates electron transport, mitochondrial metabolism and calcium homeostasis [8].”
Yang, Y., Tian, Y., Hu, S., Bi, S.-X., Li, S., Yuanjia, H., Kou, J., Qi, J., & Yu, B. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18091825 · Cited by 48
“Several recent studies indicated that increased mitochondrial fission is directly involved in cardiomyocyte death and dynamin-related protein 1 (Drp1), providing a driving force in fission, plays a pivotal role in MI injury [23].”
Background
Metadata
- Authors
- Chen, H., Chomyn, A., & Chan, D. C.
- Affiliations
- California Institute of Technology (US)
- Corresponding author
- Chan, David C.
- ORCID
- Chan, David C.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2005-07
- Volume
- 280
- Issue
- 28
- Pages
- 26185-26192
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2124140045
- Cited by
- 1,376
- References
- 28
- Citations by year
- 2026: 32 · 2025: 53 · 2024: 55 · 2023: 61 · 2022: 63 · 2021: 77 · 2020: 84 · 2019: 79 · 2018: 95 · 2017: 89 · 2016: 56 · 2015: 74 · 2014: 78 · 2013: 70 · 2012: 92
- FWCI
- 15.69
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Funders
- Muscular Dystrophy Association
- United Mitochondrial Disease Foundation
- National Institutes of Health
- National Institute of General Medical Sciences (GM11726, 1 R01 GM62967-01, R01GM062967)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- mitochondrial fusion, mitochondrial fission, Mfn1, mitofusin 2, OPA1, mitochondrial heterogeneity, mitochondrial membrane potential, cellular respiration, mitochondrial morphology, mitochondrial dysfunction
- MeSH terms
- Alleles, Animals, Fibroblasts, Genotype, Membrane Potentials, Microscopy, Fluorescence, Mitochondria, Mutation, Oxygen, Oxygen Consumption, Polyethylene Glycols, Recombinant Fusion Proteins, RNA, Time Factors, Blotting, Western, Microscopy, Confocal, GTP Phosphohydrolases, RNA Interference, Cell Proliferation, Green Fluorescent Proteins, Mice
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